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Abstract

Drug substitution is mainly economically not medically-driven; it can benefit healthcare
services but does not directly benefit individual patients. Many healthcare providers have
been promoting drug substitution in an attempt to contain their costs. This practice has
been approved and supported on the basis of the presumption that the cheaper drug is not
inferior to the more expensive one and the premise that any saving that does not
compromise the quality of care is essentially appropriate. However, substitutions become
problematic when the cheaper drug is known to have different effects and side effects, or
even when there is just uncertainty about such effects.
This thesis explores issues surrounding generic and therapeutic substitution from the
ethical, patients’ and physicians’ point of view and from the potential differences in
formulations between the branded and generic medicines. A series of studies such as a
review of the ethical issues in drug substitution, multicentre surveys to explore patients’
and physicians’ views on drug substitution and other in-vitro and in-vivo comparisons
between the actual formulations of the branded medicines and their generic counterparts
were included in this thesis. The main objective was to encourage safe and effective
generic and therapeutic substitution by validating the appropriateness and the potential
impact of these substitutions on patients’ clinical outcomes and thus to promote high
quality strategic logistic planning and effective management of drug formularies in
hospitals.
It was confirmed in this thesis that promoting generic and therapeutic substitution on
economic grounds alone is unethical because it can be potentially harmful to patients and
is incompatible with patient-centred medicine. As a consequence, multicentre surveys
were conducted to assess patients’ views on generic substitution in hospital settings. A
total of 163 renal transplant patients were surveyed using 36 multiple-choice questions at
Barts and The London Renal Transplant Clinic, in the UK. This group of patients was
specified because they may be particularly affected by drug substitution. Any small
changes in the medicinal effect of this group of patients can negatively impact their
clinical outcome. It was revealed in this survey that 84% of participating patients felt that
generic medicines were not equivalent or only equivalent sometimes and they were uncertain that generics had the same quality as branded medicines. In addition, many
patients admitted that they would refuse the generic substitution of ciclosporin when it
became available in the UK. Another multicentre survey in the United Arab Emirates
(UAE) using 188 renal patients revealed that 68% of participating patients felt that
generics were not equivalent or only equivalent sometimes, and they were uncertain that
generics had the same quality as branded medicines. Therefore, many patients admitted
that they would refuse the generic substitution of ciclosporin when become available.
These beliefs were highly marked in patients with less education, less communication
with healthcare professionals and who suspected that the cheaper drug substitution was
implemented only to save costs.
In another prescription based survey in the UAE, a random sampling of 1000 written
prescriptions was analysed to determine physicians’ attitudes towards generic medicines
and prescribing. It was explored in this study that prescribers were not yet ready to
promote appropriate generic substitution. They were still prescribing generic medicines
on occasions where health complications may occur as well as increase healthcare
expenditure. As a result, improving awareness and education among physicians is
compulsory to implement appropriate generic prescribing and substitution.
In-vitro dissolution study was also conducted in this thesis to detect any potential
differences in dissolution behaviour between the branded medicines and their generic
counterparts. A total of 37 medicines (13 innovator medicines and 24 generic
counterparts) were collected locally and internationally and tested according to the
British Pharmacopeia, European Pharmacopeia and the US Pharmacopeia with the rate of
dissolution determined by ultra-violet Spectrophotometer. It was marked in this study that
some generic medicines showed significant differences in dissolution rate at 60 and 120
minutes compared to their branded counterparts. Other generics violated the EMA and
the FDA guidelines for industry when they failed to achieve 85% dissolution at 60
minutes and to keep the same dosage form as their branded counterparts.
Moreover, a bioequivalence study was carried out in this thesis using 24 healthy
volunteers under fasting conditions to compare Resclar 500 mg (Neopharma, UAE) with
its branded Klacid® 500 mg (Abbott Laboratories Ltd, England), both are macrolide antibiotics contain 500 mg clarithromycin per tablet. It was confirmed in this study that
Resclar 500 mg met the regulatory definition of bioequivalence with Klacid® 500
mg as the innovator product based on a single dose comparative bioavailability
study under fasting conditions in the selected healthy volunteers. Therefore,
Resclar 500 mg could provide an acceptable prescribable alternative to Klacic®
500 mg.
In conclusion, the results presented in this thesis suggested that randomly and
economically-driven drug substitution can be potentially deleterious to patients and
should not be promoted. Factors such as physicians and patients education, monitoring,
severity of the disease and efficacy of generic medicines are essential to promote safe and
effective drug substitution. Thus, to achieve excellent strategic logistic planning and
effective management of drug formularies in hospitals, generic and therapeutic
substitution should be solely based on providing patients with the best possible care and quality medicines.